EL DISCURSO MAS CORTO por Bryan Dyson, ex Presidente de Coca Cola Que cosa extraa es el hombre, nacer no pide,

vivir no sabe, y morir no quiere "Imagina la vida como un juego en el que ests malabareando cinco pelotas en el aire. Estas son: Tu Trabajo,- Tu Familia,- Tu Salud,- Tus Amigos y - Tu Vida Espiritual, Y t las mantienes todas stas en el aire. Pronto te dars cuenta que el Trabajo es como una pelota de goma. Si la dejas caer, rebotar y regresar. Pero las otras cuatro pelotas: Familia, Salud, Amigos y Espritu son frgiles, como de cristal. Si dejas caer una de estas, irrevocablemente saldr astillada, marcada, mellada, daada e incluso rota. Nunca volver a ser lo mismo. Debes entender esto: apreciar y esforzarte por conseguir y cuidar lo ms valioso. Trabaja Eficientemente en el horario regular de oficina y deja el trabajo a tiempo. Dale el tiempo requerido a tu familia y a tus amigos. Haz ejercicio, come y descansa adecuadamente. Y sobre todo.....crece en vida interior, en lo espiritual, que es lo ms trascendental, porque es eterno.

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Why isnt his Asthma getting better, Doctor?

Andrew Bush
Andrew Bush, Cara Bossley, Pippa Hall Royal Brompton Hospital, London UK

Asthma: The Basics

Most children with asthma are easily treated Most respond to modest ICS doses, and get no benefit from high doses

High dose ICS may be harmful

What makes this childs asthma different and difficult to treat?

Does azithromycin work in severe asthma?

Most screened were not taking their medication or did not have asthma! JACI 2008; 122: 1138-44

Stepwise Approach to Asthma

Is the diagnosis correct?
Is the drug delivery device appropriate?

If the child is still not right:

Is it Difficult to Treat or Severe, therapy Resistant

Case Study 1
Dr Cara Bossley Paediatric Respiratory SpR Royal Brompton Hospital

MC 14 year old boy

Brittle asthma and allergic rhinitis Asthma since 1 year, worse over past 3 years Productive cough Flixotide (500mcg/day), salmeterol (100mcg/day), theophylline (250mg/day)

FEV1 57%, no reversibility

No improvement with high dose oral steroids

What would you do next?

1. Increase the dose of inhaled corticosteroid 2. Start anti-IgE therapy 3. A series of investigations to check the diagnosis is correct 4. Refer to ENT surgeons for advice 5. None of the above

What would you do next?

1. 2. Increase the dose of inhaled corticosteroid Start anti-IgE therapy

3.

A series of investigations to check the diagnosis is correct

Refer to ENT surgeons for advice None of the above

4. 5.

The productive cough, poor response to steroids and absence of bronchodilator reversibility are pointers that the diagnosis could be incorrect

Investigations
CT scan
Bronchial wall thickening, no frank bronchiectasis

Immunoglobulins
Normal total IgG/A/M

pH study - Negative Bronchoscopy

Bilateral very thick copious secretions and hyperaemia BAL: neutrophilia (66%) Haemophilus influenzae cultured

RASTs
All negative (total IgE 7) - Non-atopic

Sweat test
Negative (chloride 6)

What would you do now?

1. Give a course of oral prednisolone 2. Give a course of oral augmentin 3. Give a course of intravenous cefuroxime and gentamicin 4. Give a course of oral rifampicin 5. Commence omeprazole and domperidone

What would you do now?

1. 2. Give a course of oral prednisolone Give a course of oral augmentin

3.
4. 5.

Give a course of IV cefuroxime and gentamicin

Give a course of oral rifampicin Commence omeprazole and domperidone

Due to the poor lung function and severity of inflammation and infection seen on bronchoscopy a 2 week course of IV antibiotics was given

What further investigations should be done?

1. Exercise tolerance test
2. Psychological testing 3. Milk scan 4. Nasal nitric oxide testing 5. Blood sugar testing

What further investigations should we do?

1. 2. 3. Exercise tolerance test Psychological testing Milk scan

4. Nasal nitric oxide testing

5. Blood sugar testing

Nasal nitric oxide testing can be performed as a screening test for primary ciliary dyskinesia which can be a cause of chronic productive cough and rhinitis

Diagnosis: PRIMARY CILIARY DYSKINESIA

Nasal NO
30ppb (normal >200ppb)

Ciliary studies

Normal cilia

PCD: Absent outer dynein arms

Progress
Did very well after intravenous antibiotics Regular physiotherapy Stopped theophylline Halved flixotide dose (500 to 250mcg/d)

Spirometry improved; FEV1 57% rising to 94%

Symptomatically much better

Summary
Ongoing poorly controlled symptoms despite high dose inhaled corticosteroids and add-on therapy Chronic productive cough

Non-atopic
Low lung function, with no evidence of bronchodilator reversibility or steroid responsiveness

Other diagnoses must be considered

Difficult asthma alternative diagnoses; our experience (n=102)

One vascular ring Two had bronchiectasis idiopathic primary ciliary dyskinesia

Vascular ring

One Jobs syndrome

One severe sinus disease corrected by sinus surgery
bronchiectasis

Co-morbidities
Immune abnormality 10/74 (14%) 5/12 non-atopic patients vs 5/62 atopic children (p=0.04) 41/55 (75%) gastro-oesphageal reflux disease 4/99 (4%) airway malacia

Enlarged adenoids

5/99 (5%) enlarged adenoids

1/99 (1%) narrow right main bronchus
Tracheomalacia

Alternative / Additional diagnoses Royal London Hospital

57 difficult asthma children, 9 alternative diagnosis 3/57 (5.2%) bronchiolitis obliterans 2/57 (3.5%) functional dyspnoea 1 hyperventilation 1 vocal cord dysfunction 1/57 (1.8%) interstitial pneumonitis 2/57 (3.5%) over reporting of symptoms
Pediatr Pulmonol, 2001:31:114-120

New terminology and definitions

Problematic Severe Asthma NB: is it asthma? Are there important co-morbidities?

Stage 1 assessment

Difficult asthma Remediable factors identified Therapy adherence addressed

Genuine severe, therapy resistant asthma

Lancet 2008; 372: 1019-21

Definitions-1
Problematic Severe Asthma =
A new concept in the literature Presentation label Symptoms >3 times per week despite high dose ICS (>800 mcg BDP equivalent), LABAs, LTRAs & Theophyllines (?) Multiple severe exacerbations or a single PICU admission Brittle (chronically chaotic peak flow Type 1, catastrophic exacerbations out of the blue Type 2) Daily or alternate day prednisolone Persistent airflow limitation

Comprises two (four) categories:

Difficult asthma Severe, therapy resistant asthma (Not asthma at all wrong diagnosis) (Asthma plus co-morbidities)

Definitions-2
Difficult to treat asthma =
becomes easier when the basics are got right (adherence, environment, etc.) NOT candidates for novel therapies

Severe, therapy resistant asthma =

treatment still extremely difficult despite getting the basics right Would be potentially suitable for cytokine specific therapies

Intramuscular Triamcinolone

Visit one: MDT Assessment Drug delivery device Assess symptoms, use of rescue medication Spirometry & reversibility Induced sputum, eNO Home visit: environment School visit: bullying? Assess compliance Psychological assessment

1-2 months

Visit two: FOB Assess symptoms, use of rescue medication Spirometry & reversibility Induced sputum, eNO FOB, BAL, biopsy

4 weeks

Visit three: Decision time

The Protocol

Assess symptoms, diary card, use of rescue medication Spirometry & reversibility Induced sputum, eNO Develop treatment plan

What does a home visit achieve?

Psycho-social issues re-addressed
Anecdotally, more likely to open up 74% referrals were after home discussions

Adherence

Smoking
Allergens

Case Study 2
Pippa Hall Childrens Respiratory Nurse Royal Brompton Hospital

Child B - History
16 year old female Referred from local Paediatrician Ongoing persistent symptoms despite beyond guideline treatment Psychological issues 9 hospital admissions in past 12 months
including an admission to PICU

Treatment at Referral
Regular Medication Symbicort Montelukast Uniphylline Omalizumab Triamcinolone
400/12mcg (x3 puffs)
10mg 400mg 300mg 80mg (i/m)

BD
OD BD 2 weekly monthly

Rescue Medication 11 courses of high dose oral steroids in last year Short acting beta agonist (SABA) use >3 times daily

Investigation Results
FEV1: BDR: FeNO50:
73% predicted 26% 16ppb

Asthma Control Test (ACT): 15/25 Skin Prick Tests:

Total IgE: all negative 454

What would you do now?

1. 2. 3. 4. 5. Prescribe alternate day prednisolone Prescribe daily prednisolone Prescribe oral methotrexate Trial of subcutaneous terbutaline None of the above

What would you do now?

1. 2. 3. 4. Prescribe alternate day prednisolone Prescribe daily prednisolone Prescribe oral methotrexate Trial of subcutaneous terbutaline

5. None of the above

How did we assess adherence?

1. 2. Asked the child how often they took the medication Asked the parents how often they gave the medication Checked GP and hospital prescriptions Checked in the home for availability of in-date medications Shouted at everyone until a confession was made

3. 4. 5.

How did we assess adherence?

1. 2. Asked the child how often they took the medication Asked the parents how often they gave the medication

3.
4.
5.

Checked GP and hospital prescriptions Checked in the home for availability of in date medications
Shouted at everyone until a confession was made

How much in fact had been collected?

1. 2. 3. 4. 5. 75 100% 50 75% 25 50% <25% None at all

How much in fact had been collected?

1. 2. 3.
5.

75 100% 50 75% 25 50%

None at all

4. <25%

Interventions
Patient education
Importance of regular inhaled medication discussed

Parental supervision of medication

Parental involvement encouraged

Simplification of medication regime

Montelukast stopped

Investigations Continued
Adherence
Poor understanding of Turbohaler use GP prescription uptake <25% No parental supervision of medication

Psychology
Referred to psychologist Psychological issues not thought to be contributing to poor adherence

Outcome After 6 months

SABA use: <2 per week

FEV1:
ACT: No hospital admissions

75% predicted
20/25

1 course of high dose oral corticosteroids

Conclusion
Poor adherence to treatment was the main contributor to ongoing poorly controlled symptoms
In our cohort of difficult asthmatics1:
Prescription uptake was <50% expected in 19/59 23% did not have a complete set of in date medications available at the home visit Medication issues contributed to poor symptom control in 48%
1Thorax

Dec 2007:62(supplement 3)A21

Did they take medications?

55 (77%) had a complete set of in-date, accessible medication 44 (62%) had a good technique 34 (48%) medication issues contributed to poor control
45 40 35 30 25 20 15 10 5 0
<50 50-80 >80

Nos. %

Prescription Records

The Buck Stops Where?

Pediatrics 2008; 122: e1186-92

Case Study 3
Pippa Hall Childrens Respiratory Nurse Specialist Royal Brompton Hospital

Child A - History
15yr old boy Symptoms from 1 year of age Recent referral from local paediatrician Seretide 250mcg BD Using short acting bronchodilator (SABA) >3 daily School attendance 83% 12 courses of steroids / hospital admissions in past year

How should the child be assessed for sensitivity to allergens?

1. 2. 3. 4. 5. Skin prick testing Histamine challenge Total serum IgE Specific IgE in serum Inhalant allergy challenge

How should the child be assessed for sensitivity to allergens? 1. Skin prick testing
2. 3. Histamine challenge Total serum IgE

4. Specific IgE in serum

5. Inhalant allergy challenge

Investigation Results
FEV1: BDR: FeNO50:
61% predicted 48% 120ppb

Asthma Control Test (ACT): 7/25 Skin Prick Tests:

+ve grass, cat, dog

Home Visit
Adherence Chaotic medication regimen noted in the home Smoke Exposure Step father smokes outside (no evidence of smoke inside) Allergen Exposure 4 cats at home

Changes Following Home Visit

Medication Simplified medication regimen SMART Smoke Exposure Step father to attempt to give up smoking Allergen Exposure Cats removed from the home

What happened to the childs asthma after removal of the cats?

1. 2. 3. 4. 5. Became completely symptom free Dramatically improved control Stayed the same Got worse The child became psychotically depressed at the loss of a pet

What happened to the childs asthma after removal of the cats?

1. 3. 4. 5. Became completely symptom free Stayed the same Got worse The child became psychotically depressed at the loss of a pet

2. Dramatically improved control

6 months After Home Visit

SABA use: < once daily

FEV1:
BDR:

85% predicted
15%

FeNO50:
ACT:

68ppb
16/25

No hospital admissions or courses of high dose oral corticosteroids

Conclusions
Removing allergens in the home and simplifying medication regimen improved patient outcomes

Allergen avoidance?
HDM n=31 sensitised
Avoidance:
5 (16%) reasonable 15 (48%) some 11 (36%) none

Pets n=30 owners, 17 sensitised

Avoidance: n=2

Subclinical Allergen Exposure

Low dose allergen challenge (no decline in FEV1) Worsening AHR, sputum eosinophilia with no acute deterioration
ERJ 1998; 11: 821-7

Persistent Asthmatics

Dose-response curves for inhibition of PHA stimulation. White = no IL-2 or 4; Black = IL-2 & IL-4 IL-2 & IL-4 decrease sensitivity to the anti-proliferative effects of dexamethasone

A: Because the wrong question has been asked in the wrong population!

Lancet, April 2008

Cochrane review: Problems

Combined adult and children Intervention duration 3 weeks - 2 years Wide variety of types and scope of interventions
Mattress-only studies included

Minority showed intervention successful

Most did not reduce HDM burden

Unsuitable candidates
Not all had clinical allergy Demanding intervention did they have a problem?

Should have adjusted for season/ virus infections in small trials How many really severe asthmatics?

Viruses, Asthma, Allergens

84 children, 3-17yr Acute exacerbation of asthma vs. stable asthma vs. controls
20 18 16 14 12 10 8 6 4 2 0

P<0.0001

SPT, RASTs, home allergen levels

Viral PCR on nasal lavage Thorax 2006; 61: 376-82

OR (mv)

+ -

- + + + Sensitized - + - + Exposed + - + + Virus

Summary and Conclusions

Do not forget the obvious
Wrong diagnosis Not taking treatment Cannot use device

Ask the key question: What makes this asthma difficult? Consider environmental causes of steroid resistance

Only then think of escalating therapy